Interventions to improve linkage along the HIV-tuberculosis care cascades in low- and middle-income countries: A systematic review and meta-analysis

Introduction In support of global targets to end HIV/AIDS and tuberculosis (TB) by 2030, we reviewed interventions aiming to improve TB case-detection and anti-TB treatment among people living with HIV (PLHIV) and HIV testing and antiretroviral treatment initiation among people with TB disease in low- and middle-income countries (LMICs). Methods We conducted a systematic review of comparative (quasi-)experimental interventional studies published in Medline or EMBASE between January 2003-July 2021. We performed random-effects effect meta-analyses (DerSimonian and Laird method) for interventions that were homogenous (based on intervention descriptions); for others we narratively synthesized the intervention effect. Studies were assessed using ROBINS-I, Cochrane Risk-of-Bias, and GRADE. (PROSPERO #CRD42018109629). Results Of 21,516 retrieved studies, 23 were included, contributing 53 arms and 84,884 participants from 4 continents. Five interventions were analyzed: co-location of test and/or treatment services; patient education and counselling; dedicated personnel; peer support; and financial support. A majority were implemented in primary health facilities (n = 22) and reported on HIV outcomes in people with TB (n = 18). Service co-location had the most consistent positive effect on HIV testing and treatment initiation among people with TB, and TB case-detection among PLHIV. Other interventions were heterogenous, implemented concurrent with standard-of-care strategies and/or diverse facility-level improvements, and produced mixed effects. Operational system, human resource, and/or laboratory strengthening were common within successful interventions. Most studies had a moderate to serious risk of bias. Conclusions This review provides operational clarity on intervention models that can support early linkages between the TB and HIV care cascades. The findings have supported the World Health Organization 2020 HIV Service Delivery Guidelines update. Further research is needed to evaluate the distinct effect of education and counselling, financial support, and dedicated personnel interventions, and to explore the role of community-based, virtual, and differentiated service delivery models in addressing TB-HIV co-morbidity.


PROSPERO International prospective register of systematic reviews
Give details of the individuals, organizations, groups or other legal entities who take responsibility for initiating, managing, sponsoring and/or financing the review. Include any unique identification numbers assigned to the review by the individuals or bodies listed. State the question(s) to be addressed by the review, clearly and precisely. Review questions may be specific or broad. It may be appropriate to break very broad questions down into a series of related more specific questions. Questions may be framed or refined using PI(E)COS where relevant. In people living with HIV or active TB, what interventions improve identification of active TB and HIV coinfection, respectively, and linkage to treatment for co-infection? Give details of the sources to be searched, search dates (from and to), and any restrictions (e.g. language or publication period). The full search strategy is not required, but may be supplied as a link or attachment. A primary search will be conducted using two databases: MEDLINE (using Ovid or PubMed), and EMBASE. We will also include original studies from the reference lists of both 1) published systematic reviews that relate to the TB and HIV diagnostic and treatment initiation care cascades (this includes reviews of TB screening and diagnostic interventions, HIV testing intervention, and TB-HIV service integration interventions) and 2) all articles ultimately included in our study. The search strategy will be developed in consultation with an expert librarian at McGill University, Canada, and implemented by the research team. It will combine terms, keywords and subject headings based on the following concepts: 1) tuberculosis; 2) HIV or AIDS; 2) screening / testing / diagnosis / case-detection / notification; 3) treatment initiation / prescription / commencement; 4) referral / linkage / integration / coordination / collaboration. Articles retrieved from the primary search will be combined in an Endnote file, and duplicates removed. The search strategy will be limited to studies published in English since 2003 (following the release of Stop TB'S "Guidelines for implementing collaborative TB/HIV programme activities"), and reporting primary data from LMICs. 113 words remaining 17. URL to search strategy.
Page: 3 / 10 PROSPERO International prospective register of systematic reviews Give a link to the search strategy or an example of a search strategy for a specific database if available (including the keywords that will be used in the search strategies).
Alternatively, upload your search strategy to CRD in pdf format. Please note that by doing so you are consenting to the file being made publicly accessible.
Do not make this file publicly available until the review is complete 18. * Condition or domain being studied.
Give a short description of the disease, condition or healthcare domain being studied. This could include health and wellbeing outcomes. Tuberculosis (TB) and Human Immunodeficiency Virus (HIV) diagnosis and treatment initiation 189 words remaining 19. * Participants/population. Give summary criteria for the participants or populations being studied by the review. The preferred format includes details of both inclusion and exclusion criteria. Inclusions: a. Persons living with HIV in care (newly diagnosed with HIV, with an existing HIV diagnosis, and/or receiving ART) b. Persons with active TB or TB disease in care (newly diagnosed with active TB or TB disease, with an existing TB diagnosis, based on culture / smear, GeneXpert result, or clinical diagnosis) c. Eligible persons of all ages (children ( less than 18 y) and adults) Exclusions: none 133 words remaining 20. * Intervention(s), exposure(s).
Give full and clear descriptions or definitions of the nature of the interventions or the exposures to be reviewed. Include: a. Any intervention that targets patients, providers or programs and impacts linkage to TB treatment and care among people living with HIV (i.e., diagnosis of active TB, entry into TB care, TB treatment initiation) b. Any intervention that targets patients, providers or programs and impacts linkage to HIV treatment and care among people with active TB (i.e., diagnosis of HIV, entry into HIV care, ART initiation) Exclude: a. Interventions to prevent incidence of active TB among people living with HIV (e.g., LTBI screening and treatment) b. Biomedical interventions (e.g., drug trial or drug test, diagnostic test or diagnostic tool) c. Population level interventions (e.g., community awareness campaigns, general TB or HIV screening and testing interventions) 84 words remaining 21. * Comparator(s)/control. Where relevant, give details of the alternatives against which the main subject/topic of the review will be compared (e.g. another intervention or a non-exposed control group). The preferred format includes details of both inclusion and exclusion criteria. Local standard of care for TB/HIV 194 words remaining 22. * Types of study to be included.
Give details of the types of study (study designs) eligible for inclusion in the review. If there are no restrictions on the types of study design eligible for inclusion, or certain study types are excluded, this should be stated. The preferred format includes details of both inclusion and exclusion criteria. We will include original studies (i.e., studies reporting primary data, cohort studies, randomized controlled trials (RCT) and quasi-randomized controlled trials).
Page: 4 / 10 PROSPERO International prospective register of systematic reviews We will exclude secondary analyses or reviews, commentaries, editorials, case-reports, studies with 10 participants, case-control studies, qualitative studies, unpublished studies, and studies published in non peerreviewed journals. 100 words remaining 23. Context.
Give summary details of the setting and other relevant characteristics which help define the inclusion or exclusion criteria. We will included only studies published in 2003 or later (following the release of Stop TB'S "Guidelines for implementing collaborative TB/HIV programme activities") and discussing interventions within low-and middle-income countries. 219 words remaining 24. * Main outcome(s).
Give the pre-specified main (most important) outcomes of the review, including details of how the outcome is defined and measured and when these measurement are made, if these are part of the review inclusion criteria. There are four primary outcomes: 1. TB diagnosis (based on culture / smear / Xpert, or clinical diagnosis) 2. TB treatment initiation (any regimen used for ACTIVE TB; excludes preventative treatment (isoniazid)) 3. HIV diagnosis (based on antigen / antibody / NAT test) 4. ART initiation (any regimen used for HIV treatment; excludes cotrimoxazole preventative therapy (CPT), Pre-Exposure Prophylaxis (PrEP), and TasP (Treatment as Prevention)) 138 words remaining Timing and effect measures n/a 199 words remaining 25. * Additional outcome(s).
List the pre-specified additional outcomes of the review, with a similar level of detail to that required for main outcomes. Where there are no additional outcomes please state 'None' or 'Not applicable' as appropriate to the review Secondary outcomes* include: 1. Diagnostic or treatment delay 2. Death *Included studies must ALSO report on a primary outcome. Studies only reporting on a secondary outcome will be excluded. 273 words remaining Timing and effect measures n/a 299 words remaining 26. Data extraction (selection and coding).
Give the procedure for selecting studies for the review and extracting data, including the number of researchers involved and how discrepancies will be resolved. List the data to be extracted. A data collection form will be developed and pilot-tested by the two independent reviewers, and refined or clarified as necessary. After finalizing each form, the two reviewers will use it to independently extract data from all eligible studies. If there are multiple reports of the same study, data from all reports will be extracted directly into a single data collection form. Any disagreement between reviewers will be resolved through discussion if possible. If the disagreement persists, it will be resolved in discussion with a third independent reviewer. When necessary, study authors will be contacted to obtain information required to resolve a disagreement. If a disagreement cannot be resolved after third-party consultation and after contacting study authors, it will be reported in the final review. All disagreements and their resolution will be clearly documented. 167 words remaining 27. * Risk of bias (quality) assessment.
Page: 5 / 10 PROSPERO International prospective register of systematic reviews State whether and how risk of bias will be assessed (including the number of researchers involved and how discrepancies will be resolved), how the quality of individual studies will be assessed, and whether and how this will influence the planned synthesis. Two reviewers will independently appraise the quality of all included studies, on a distinct form, using the Cochrane risk of bias tool for RCTs, the ROBINS-I Tool for observational studies. The appropriateness of the statistical model used within studies will also be assessed, particularly relevant for quasi-experimental studies. The quality of each study will be classified as: very low, low, moderate or high. Any discrepancies between reviewers will be resolved in discussion or in consultation with a third reviewer. When necessary, study authors will be contacted to obtain missing information needed for quality assessment; in such cases, we will strive for open-ended questions in order to reduce the risk of overly positive responses. 87 words remaining 28. * Strategy for data synthesis.
Give the planned general approach to synthesis, e.g. whether aggregate or individual participant data will be used and whether a quantitative or narrative (descriptive) synthesis is planned. It is acceptable to state that a quantitative synthesis will be used if the included studies are sufficiently homogenous. Given the anticipated diversity in types of interventions, summary effect measures will be estimated separately for each type of intervention (e.g. education and counselling; reminder and monitoring systems; financial incentives; etc.). For types of interventions and outcomes with sufficient number of studies, we will report pooled effect measures for those interventions (e.g. risk or rate ratios). The decision on whether metaanalyses should be conducted, and on which interventions and outcomes, will be arrived at through a discussion amongst the independent reviewers and research team. Considerations will include: number of studies; risk of biases of the potential studies to be included in a meta-analysis; methodological heterogeneity of the studies (participants, setting, study design, and modeling approach). In addition to any meta-analyses, we will report ranges of effect estimates for each type of intervention.
Meta-analyses will be done using a random effects model with R (V3.4.4). 155 words remaining 29. * Analysis of subgroups or subsets.
Give details of any plans for the separate presentation, exploration or analysis of different types of participants (e.g. by age, disease status, ethnicity, socioeconomic status, presence or absence or comorbidities); different types of intervention (e.g. drug dose, presence or absence of particular components of intervention); different settings (e.g. country, acute or primary care sector, professional or family care); or different types of study (e.g. randomised or non-randomised). We also plan to explore subgroup analyses for each of the following variables: -study setting (e.g. by WHO region, rural/urban, income level, -participant sex -participant age group -type of facility (e.g. clinic, hospital, community-based), and -type of intervention (e.g. patient-or provider-or systems-focused, psychosocial or economic intervention) Other potential subgroup analyses (contingent on range of data collected in included studies) include: baseline CD4 cell counts; severity of TB disease; site of TB (extrapulmonary or pulmonary); underlying TB or HIV drug resistance, previous TB and HIV treatment history; comorbidities (such as diabetes and mental illnesses, etc.), and specific population groups (such as prisoners, refugees, migrant workers, health care workers, injection drug users, etc.).
If appropriate, we will also conduct additional analyses to assess high-vs. low-quality studies, sensitivity analyses for each meta-analysis by removing each study one at a time to evaluate its impact on the pooled estimate, and publication bias using funnel plots and the Egger test. 92 words remaining 30. * Type and method of review.
Select the type of review and the review method from the lists below. Select the health area(s) of interest for your review.